Effects of Study Drug on Serum and Plasma VEGF, VEGFR, and Cytokine Profiles [ Time Frame: On the first day of every 28-day cycle of treatment, Day 15, and treatment discontinuation ] [ Designated as safety issue: No ]

Effects of Study Drug on HIV and KSHV Viral Loads [ Time Frame: Screening, end of cycle 1, end of every third cycle thereafter, and treatment discontinuation ] [ Designated as safety issue: No ]

Effects of Study Drug on T-lymphocyte Subsets (i.e., CD4 and CD8) [ Time Frame: Screening, day 29, every 3 cycles thereafter, and at treatment discontinuation ] [ Designated as safety issue: No ]

Effects of Study Drug on VEGF, VEGFR-2 and -3, Phospho-Akt, p53, and HIF-1α Expression and Tumor Cell Proliferation, as Measured by Ki-67 Staining, in Tumor Biopsy Samples [ Time Frame: Screening and day 28 ] [ Designated as safety issue: No ]

20 mg capsules to be taken by mouth BID. Three dose levels will be evaluated: 40 mg, 80mg, and 100mg BID. Subjects will receive PTC299 in consecutive 28-day cycles for a maximum of 12 cycles.

Genetic: gene expression analysis

To describe the effects of PTC299 on viral gene expression and cellular gene transcription in KS tumor biopsies using real-time QPCR-based profiling.

Genetic: polymerase chain reaction

To describe the effects of PTC299 on viral gene expression and cellular gene transcription in KS tumor biopsies using real-time QPCR-based profiling.

Genetic: protein expression analysis

To describe the effects of PTC299 on viral gene expression and cellular gene transcription in KS tumor biopsies using real-time QPCR-based profiling.

Other: immunohistochemistry staining method

To describe the effects of PTC299 on KS tumor biopsies with respect to expression of VEGF, the VEGFR-2 and -3, phospho-Akt, p53, HIF-1α and proliferation, measured by Ki-67 staining.

Other: laboratory biomarker analysis

To describe the effects of PTC299 on KS tumor biopsies with respect to expression of VEGF, the VEGFR-2 and -3, phospho-Akt, p53, HIF-1α and proliferation, measured by Ki-67 staining.

Other: pharmacological study

To describe the pharmacokinetics of PTC299 in patients with HIV-associated KS. To describe the effects of PTC299 on circulating VEGF, VEGFR and cytokine levels in patients with HIV-associated KS.

Procedure: biopsy

To describe the effects of PTC299 on KS tumor biopsies with respect to expression of VEGF, the VEGFR-2 and -3, phospho-Akt, p53, HIF-1α and proliferation, measured by Ki-67 staining.

Detailed Description:

OBJECTIVES:

Primary

To define the safety and toxicity of anti-VEGF small molecule PTC299 in patients with HIV-related Kaposi sarcoma.

To establish the maximum tolerated dose of this drug in these patients.

To estimate the response rate in patients treated with this drug.

Secondary

To describe the pharmacokinetics of this drug in these patients.

To describe the effects of this drug on serum and plasma VEGF, VEGFR, and cytokine profiles in these patients.

To describe the effects of this drug on HIV and KSHV viral loads in these patients.

To describe the effects of this drug on T-lymphocyte subsets (i.e., CD4 and CD8) in these patients.

To describe the effects of this drug on VEGF, VEGFR-2 and -3, phospho-Akt, p53, and HIF-1α expression and tumor cell proliferation, as measured by Ki-67 staining, in tumor biopsy samples obtained from these patients.

To describe the effects of this drug on viral gene expression and cellular gene transcription, as measured by real-time quantitative PCR-based profiling, in tumor biopsy samples obtained from these patients.

OUTLINE: This is a multicenter, phase I dose-escalation study of anti-VEGF small molecule PTC299 followed by a phase II study.

Patients receive oral anti-VEGF small molecule PTC299 twice daily on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients who do not demonstrate an objective response of their Kaposi sarcoma (KS) lesions after 6 courses of treatment are removed from the study.

Patients with GI and/or pulmonary involvement must be asymptomatic or minimally symptomatic and not require systemic cytotoxic chemotherapy

Has at least five bidimensionally measurable cutaneous lesions that have not been previously irradiated AND can be used as indicator lesions

Must have a sufficient number of non-indicator cutaneous lesions measuring ≥ 4 x 4 mm available to obtain a total of four 3-mm punch biopsies (two at baseline and two during the course of study treatment)

Serologic documentation of HIV infection, as evidenced by positive ELISA, western blot, or other federally approved licensed HIV test OR a detectable blood level of HIV RNA

Patients receiving antiretroviral therapy for HIV infection are eligible provided they have been on a stable regimen for ≥ 12 weeks prior to study entry AND there is no evidence of improvement in KS during those 12 weeks or there is evidence of progression of KS within the immediate 4 weeks prior to study entry

No symptomatic visceral KS requiring cytotoxic therapy

PATIENT CHARACTERISTICS:

Karnofsky performance status 60-100%

Life expectancy ≥ 3 months

Absolute neutrophil count ≥ 1,000/mm³

Platelet count ≥ 75,000/mm³

Hemoglobin ≥ 8 g/dL

Creatinine ≤ 2.0 mg/dL

Total bilirubin normal (grade 0)

No specific limit of total serum bilirubin for patient receiveing indinavir or atazanavir therapy AND direct serum bilirubin ≤ 30% of total bilirubin

AST and ALT ≤ 2.5 times upper limit of normal (grade 1)

INR and aPTT normal

Proteinuria < 2+

Not pregnant or nursing

Negative pregnancy test

Fertile patients must use effective barrier contraception during and for up to 3 months after completion of study treatment

Capable of complying with the study, in the opinion of the investigator

No acute, active opportunistic infection (other than oral thrush or genital herpes) within the past 14 days

No history of or ongoing clinically significant illness, medical condition, surgical history, physical finding, ECG finding, or laboratory abnormality that, in the opinion of the investigator, could affect the safety of the patient, alter the absorption of the study drug, or impair the assessment of study results

PRIOR CONCURRENT THERAPY:

More than 4 weeks since prior and no other concurrent anti-neoplastic therapy for KS, including chemotherapy, radiotherapy, local therapy, or biological therapy

More than 60 days since prior local therapy for any KS-indicator lesion unless the lesion has clearly progressed since treatment

Any prior local therapy for indicator lesions (regardless of the elapsed time) should not be allowed unless there is evidence of clear-cut progression of that lesion

More than 28 days since prior and no other concurrent investigational drugs or therapy (other than antiretroviral therapy or agents available on a treatment IND)

More than 30 days since prior major surgery and recovered

More than 14 days since prior treatment for an acute infection (other than oral thrush or genital herpes) or other serious medical illness

No concurrent surgical procedures

No concurrent systemic corticosteroid therapy, other than replacement doses

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00686842

Locations

United States, California

Rebecca and John Moores UCSD Cancer Center

La Jolla, California, United States, 92093-0658

UCLA Clinical AIDS Research and Education (CARE) Center

Los Angeles, California, United States, 90095-1793

USC/Norris Comprehensive Cancer Center and Hospital

Los Angeles, California, United States, 90033-1048

United States, Hawaii

Cancer Research Center of Hawaii

Honolulu, Hawaii, United States, 96813

United States, Massachusetts

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

United States, New York

Memorial Sloan-Kettering Cancer Center

New York, New York, United States, 10065

United States, Ohio

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center